Di- and tri-substituted thiazoles

ABSTRACT

Di- and tri-substituted thiazoles, one substituent being a 3-amino-2-OR-propoxy group are disclosed. The thiazoles have β-adrenergic blocking activity.

This is a continuation of copending U.S. application Ser. No. 802,403,filed June 1, 1977 now abandoned.

BACKGROUND OF THE INVENTION

The present invention involves novel di- and tri- substituted thiazoleshaving pharmaceutical activity as β-adrenergic blocking agent.

Thiazoles having an aminohydroxypropoxy substituent in the 2-positionwith or without a specific additional substituent in the 4 or5-position, are known and are taught to have β-adrenergic stimulatingactivity (U.S. Pat. No. 3,850,945). Thiazoles having anaminohydroxypropoxy substituent in the 4 or 5-position with noadditional sbustitution are also known and are taught to haveβ-adrenergic stimulating activity (U.S. Pat. Nos. 3,850,947, 3,850,946).Thiazoles having the aminohydroxypropoxy substituent in the 2-positionwith an aminocarbonyl, formamido, substituted oxycarbonyl amino group inthe 4 or 5-position, are known and taught to have β-adrenergic blockingactivity (U.S. Pat. No. 3,897,411). Thiazoles having the followingformula ##STR1## are known and are taught to be β-adrenergic blockingagents. (U.S. Pat. No. 3,897,442). Thiazoles of the formula ##STR2## areknown and are taught to block β-adrenergic receptors (U.S. Pat. No.3,932,400).

Novel di- and tri-substituted thiazoles having a 4(3-amino-2-OR-propoxy)substituent have been discovered. The thiazoles are active asβ-adrenergic blocking agents.

SUMMARY OF THE INVENTION

Di- and tri- substituted thiazoles having a 4(3-amino-2-OR-propoxy)group and their pharmaceutical use.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention is compounds having the formula##STR3## and pharmaceutically acceptable salts thereof, wherein R ishydrogen or C₂ -C₁₂ acyl,

R₁ is C₁ -C₁₂ alkyl,

R₂ is hydrogen, CF₃, C₆ -C₁₂ carbocyclic aryl, 6-membered-N-heteroaryl,C₁ -C₆ alkyl, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, thienyl and furfuryl,

R₃ is C₁ -C₆ alkyl, --COOC₁ -C₆ alkyl, COOC₆ -C₁₂ aryl, cyano, C₆ -C₁₂carbocyclic aryl, CF₃ or ##STR4## wherein R₄ and R₅ are independentlyselected from H and C₁ -C₆ alkyl or are joined forming ##STR5## providedthat when R₂ is phenyl, R₃ is other than C₁ -C₆ alkyl or COOC₁ -C₆alkyl.

The pharmaceutically acceptable salts are the acid addition salts of theformula I free base. Suitable acids include organic as well as inorganicacids. Examples of useful organic acids are carboxylic acids such asacetic acid, pamoic acid, maleic acid, succinic acid, citric acid,tartaric acid, oxalic acid, malic acid, pivalic acid, heptanoic acid,lauric acid, propanoic acid, pelargonic acid, oleic acid and the like,and non-carboxylic acids such as isethionic acid. Examples of usefulinorganic acids are the hydrogen halides i.e., HCl, HBr, HI, phosphoricacid, sulfuric acid, and the like. The hydrohalide salts especially thehydrocylorides and maleic acids, especially the hydrogen maleate, arepreferred.

R may be hydrogen or C₂ -C₁₂ acyl. The C₂ -C₁₂ acyl groups includealkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl,succinoyl and the like--and carbocyclic aroyl groups such as benzoyl, 1-or 2-naphthoyl, p-methylbenzoyl, p-phenylbenzoyl and the like. The C₂-C₆ alkanoyl and benzoyl groups are preferred acyl groups. Hydrogen is amost preferred R group.

The R₁ substituent includes C₁ -C₁₂ alkyl groups and preferably the C₁-C₆ alkyl groups. The alkyl groups are exemplified by methyl, C₁₂ H₂₅,hexyl, 2-ethylhexyl, isopropyl, sec-butyl, heptyl and the like. The C₃₋₄branched chain alkyl R₁ groups are more preferred, with t-butyl being amost preferred group.

R₂ includes H, CF₃, C₆ -C₁₂ carbocyclic aryl such as phenyl,monosubstituted phenyl e.g. p-tolyl, o-halophenyl, p-nitrophenyl,p-methoxyphenyl and p-halophenyl; indanyl; 1- or 2-naphthyl and thelike, 6-membered-N-heteroaryl such as 2-, 3- or 4-pyridyl, pyridazinyl,pyrazinyl, pyrimidinyl and the like; thienyl, furfuryl C₁ -C₆ alkyl,e.g. methyl, n-hexyl, isopropyl, sec-butyl, ethyl and the like, C₁ -C₆alkylthio, and the sulfinyl and sulfonyl derivatives exemplified by C₂H₅ --S, C₄ H₉ --SO, C₆ --H₁₃ --SO₂, CH(CH₃)₂ --SO₂, CH₃ --SO, t-butyl-Sand the like. Preferred R₂ groups are hydrogen, C₁ -C₆ alkyl and C₁ -C₆-alkylthio, especially CH₃ --S.

The R₃ substituent includes CF₃, C₁ -C₆ alkyl, CN, C₆ -C₁₂ carbocyclicaryl such as phenyl, carboxylic acid esters and amides. The C₁ -C₆ alkylgroup is exemplified by CH₃, isopropyl, and the like. The ester group isC₁ -C₆ -alkylester exemplified by --COOCH₃, --COOC₆ H₁₃, --COOCH(CH₃)₂,--COOC₂ H₅ and the like and C₆ -C₁₂ arylester, preferably carbocyclicaryl, exemplified by C₆ H₅ --OOC, p--CH₃ --C₆ H₄ --OOC--, p--C₆ H₅ --C₆H₄ --OOC--, C₉ H₉ --OOC-- and the like. The amide group includes--CONH₂, C₁ -C₆ substituted amide groups such as --CON(CH₃)₂, --CON(C₆H₁₃)₂, --CONHC₂ H₅, --CON (sec. butyl)₂ and the like and carbonylheterocyclic groups such as ##STR6## Of the R₃ groups, CN, CF₃ andamide, especially CONH₂, are preferred.

The formula I compounds have a chiral center, (at the 2 carbon in thepropoxy substituent) which confers optical activity. The optical isomersare designated conventionally as L and D, l and d, + and -, S and R orby combinations of these symbols. Where the formula or compound nameherein carries no specific designation, the formula or name includes theindividual isomers, the mixtures thereof and racemates.

The thiazole compounds which are preferred have the formula ##STR7##Formula II compounds where R₂ is H, C₁ -C₆ alkylthio, preferably CH₃--S--, or said heteroaryl groups, especially pyridyl, R₃ is CN, CF₃,amide, C₁ -C₆ alkyl or said ester group and R₁ is C₁ -C₆ alkylespecially C₃ -C₄ branched alkyl are more preferred. In most preferredformula II compounds, R₂ is said alkylthio or heteroaryl, R₃ is CN, CF₃,CONH₂, C₁ -C₆ alkyl or said ester and R₁ is C₃ -C₄ branched alkyl.

Another preferred group of thiazoles has the formula ##STR8## where R₂is H, C₁ -C₆ alkyl, C₁ -C₆ alkylthio or pyridyl, R₃ is CN, CF₃, C₁ -C₆alkyl or CONH. In more preferred formula III thiazoles, said branchedalkyl is tert.-butyl, R₂ is H, CH₃, CH₃ S or pyridyl, and R₃ is CN, CH₃,CONH₂ or CF₃ and the thiazoles where said branched alkyl is tert.-butyl,R₂ is H, CH₃ S or pyridyl and R₃ is CN or CONH₂ are particularlypreferred.

Of the optical isomers those having the S-isomer configuration arepreferred.

The thiazoles of the present invention have β-adrenergic blockingactivity. This was determined in an in-vivo test using dogs as the testanimals. In this test, representative thiazole compounds, were found tocounteract the β-adrenergic stimulating effect of isoproterenol.

Certain of the present thiazoles also exhibit an antihypertensive effectof immediate onset when administered to a spontaneously hypertensive(SH) rat. Representative of such compounds are those having the formula##STR9##

The present thiazoles also show random vasodilator activity.

The present thiazole compounds will effect β-adrenergic blockade inhumans. This β-adrenergic blocking effect is useful in the therapeutictreatment of various cardiovascular conditions such as angina pectoris,arrhythmia etc. In administering these formula I compounds for theirβ-adrenergic blocking effect, the daily dosage may range from about 1.5mg. to about 3000 mg. Preferred daily dosages are about 6.5 mg. to about200 mg. Conventional dosage forms suitable for oral as well asparenteral, e.g. intravenous, intraperitoneal etc., administration areused. Oral dosage forms include tablets, capsules, troches, liquidformulations e.g. solutions, emulsions, elixirs, etc.--parenteral dosageforms include liquid formulations especially solutions. The compositionsare prepared using conventional procedures and compounding ingredientssuch as starch, sterile water, flavoring additives, antioxidants,binders, vegetable oils, sweetening agents, glycerine and the like.

Thiazoles which exhibit the immediate onset antihypertensive activityare useful for treating hypertensive humans at daily dosages rangingfrom about 100 to about 3000 mg. administered in oral or parenteraldosage forms.

The present thiazoles can be prepared by any convenient process.

One such process involves the coupling of a suitably substitutedthiazole with a suitably substituted oxazolidine and hydrolyzing thereaction product obtained. This process is illustrated by the followingset of reaction equations: ##STR10## Z is an alkyl or arylsulfonylgroup. Examples of sulfonyl groups are CH₃ --SO₂ --, C₆ H₅ --SO₂ --, NO₂--C₆ H₄ --SO₂ --, p--CH₃ --C₆ H₄ --SO₂ --, mesitylene--SO₂ --, CH₃ O--C₆H₄ --SO₂ --, trichlorobenzene--SO₂ --, C₁₆ H₃₃ --SO₂ -- and the like.Suitable bases are alkali metal bases such as K₂ CO₃, K--O--C(CH₃)₃,NaH, organolithiums e.g. phenyllithium, n-butyllithium, lithiumdiisopropyl amide and the like.

R₆ is hydrogen or other C₁ -C₁₂ alkyl or C₆ -C₁₂ carbocyclic arylresidue of any suitable aldehyde ##STR11## Examples of suitablealdehydes are the aryl aldehydes such as benzaldehyde, naphthaldehyde4-phenylbenzaldehyde, furfural, bromobenzaldehyde, tolualdehyde,mesitaldehyde and the like, or an alkanal such as acetaldehyde,butyraldehyde ##STR12## and the like. The process for preparingoxazolidines where Z is hydrogen (and a related coupling reaction) isdisclosed in U.S. Pat. Nos. 3,718,647 and 3,657,237 and to the extentnecessary the pertinent disclosure is incorporated herein by reference.

The coupling reaction can be carried out at temperatures ranging fromabout 0° C. to about 130° C. A temperature range of about 50° C. toabout 130° C. is preferred. The reaction is generally carried out in asolvent. Any suitable solvent may be used. Examples of useful solventsare dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide,tert.butanol, dioxane, toluene, acetone and the like. The hydrolysis iscarried out using a conventional acid system e.g. by treatment with asolution of any suitable acid such as HCl, H₂ SO₄, CH₃ COOH and thelike. The hydrolysis product can be directly obtained as the salt of theacid used for the hydrolysis. Ordinarily, the product IA is recovered asthe free base after conventional neutralization of the salt.

The coupling reaction is ordinarily carried out at atmospheric pressure.Higher pressures may be used if desired.

When a racemic oxazolidine (formula V) is used as a reactant, theproduct is obtained as a racemate. The racemate may be separated intoits individual enantiomers by conventional resolution techniques.

When R₆ in the oxazolidine (e.g. formula V or VI) is other thanhydrogen, in addition to the chiral center at oxazolidine position 5there is a second chiral center at position 2. However, whenever anoxazolidine is designated e.g. as (S), (R) or (R,S), this designationrefers only to the optical configuration around the carbon atom at the 5position.

By using a single optical isomer of the formula V oxazolidine in theabove reaction the thiazole product (IA) may be obtained directly as asingle enantiomer. This provides a convenient way for directly preparingindividual isomers of the present thiazoles.

Thiazoles represented by formula I wherein R is other than hydrogen areconveniently prepared by treating the corresponding thiazole where R ishydrogen with an appropriate acylating agent such as an acyl halide,e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride,p-methoxybenzoyl chloride, an anhydride e.g. acetic anhydride and thelike. The reaction is illustrated by the following equation: ##STR13##

The compounds of the present invention also include the pharmaceuticallyacceptable salts of the novel thiazoles. These salts are convenientlyprepared e.g. by treating the thiazole with an appropriate amount of auseful acid, generally in a suitable solvent.

Additional processes for preparing thiazoles with certain othersubstituents are illustrated by the following equation sequences.Conventional reaction conditions are employed. The symbol L representsthe --CH₂ --CHOR--CH₂ --NR₁ group. ##STR14##

The thiazoles having an alkylsulfinyl or alkylsulfonyl substituent areprepared by oxidizing the corresponding C₁ -C₆ alkylthio containingcompound. Any suitable oxidizing agent, e.g. H₂ O₂, may be used. Thefollowing equation illustrates the reaction ##STR15##

The 4-OH substituted thiazole intermediates used in the oxazolidinecoupling reaction described above are prepared using conventionalprocesses illustrated by the following equations:

The following examples illustrate preparation of representativethiazoles of the present invention. All temperatures are in °C.

EXAMPLE 1 (S)5-Methyl-2-phenyl-4(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogenmaleate salt

To a stirred solution of (S)2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (2.5 g., 0.01 m)and dry pyridine (5 ml.) is added portionwise p-toluenesulfonyl chloride(2.0 g., 0.011 m), while maintaining the temperature of the reactionbelow 30° C. After the addition, the mixture is stirred at roomtemperature for 3 hours. To the solid mixture is added a solution of K₂CO₃ (1.4 g., 0.01 m) in H₂ O (10 ml.) and the solution extracted withCHCl₃ (3×25 ml.). The organic layer is dried over Na₂ SO₄, filtered andconcentrated to dryness below 50° C. to yield the tosylate of (S)2-phenyl-3-tert.butylamino-2-hydroxymethyloxazolidine which is used inthe next step without further purification.

Into a dry flask under N₂ is added 4-hydroxy-5-methyl-2-phenylthiazole(1.91 g., 0.1 m), dimethylformamide (DMF) (20 ml.) and NaH (50% mineraloil, 0.5 g., 0.01 m). After stirring at room temperature for 15 minutes,the tosylate of (S)2-phenyl-3-tert.-butylamino-5-hydroxymethyloxazolidine (0.01 m) in DMF(20 ml.) is added and the solution heated under reflux with stirring.After 12 hours, the solvent is removed under reduced pressure (1.5 mm).The residue is treated with 1 N HCl (100 ml.) and heated on a steam bathfor 3/4 hours. After cooling, the aqueous layer is extracted with ether(2×50 ml.), neutralized with saturated Na₂ CO₃, and extracted with CHCl₃(3×100 ml.). The organic layer is dried over Na₂ SO₄, filtered andconcentrated to dryness. The residue is chromatographed on silica gel 60and the product eluted with 10% MeOH--CHCl₃. The crude product iscrystallized with maleic acid in isopropanol (IPA)-MeOH to yield 0.25 g.(6%) of 5-methyl-2-phenyl-4(3-tert.butylamino-2-hydroxypropoxy) thiazolehydrogen maleate salt, m.p. 174°-6° C.

EXAMPLE 2 (S)5-Carbamoyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy) thiazolehydrogen maleate salt

A. Into a dry flask under N₂ is added ethyl4-hydroxy-2-phenylthiazole-5-carboxylate (2.5 g., 0.01 m), DMF (20 ml.)and NaH (50% mineral oil, 0.5 g., 0.01 m). After stirring for 15minutes, a solution of the tosylate of (S)2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.01 m) in DMF(15 ml.) is added at 0°-4° C. and the solution heated with stirring at100° C. After 15 hours, the solution is cooled to 0°-10° C., poured intoH₂ O (100 ml.) and extracted with ether (3×100 ml.). The organic layeris extracted with 1 N HCl (2×50 ml.) and the acid layer added to NaOAc(8.2 g., 0.1 m). After 5 hours, the solution is extracted with ether(2×50 ml.). The aqueous layer is neutralized with saturated Na₂ CO₃ andextracted with CHCl₃ (3×100 ml.). The organic layer is dried over Na₂SO₄, filtered and concentrated to dryness. The residue ischromatographed on alumina (activity grade II, E. Merck) and the producteluted with 25% hexane-CHCl₃. The crude product is crystallized withmaleic acid in CH₃ CN-ether to yield 0.7 g. (14%) of (S)ethyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylatehydrogen maleate, m.p. 165°-7° C.

B. A mixture of (S)ethyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate,obtained by neutralizing the product from A., (4.7 g., 0.012 m), MeOH(90 ml.) and liquid NH₃ (22 g.) is heated at 100° C. in a sealed tube.After 24 hours, the reaction mixture is concentrated to dryness. Theresidue is chromatographed on alumina (activity grade II, E. Merck) andthe product eluted with CHCl₃. The crude product is crystallized withmaleic acid in IPA to yield 1.65 g. (30%) of (S)5-carbamoyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy) thiazolehydrogen maleate salt, m.p. 184°-5° C.

EXAMPLE 3 (S) 5-Cyano-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate

To triphenylphosphine oxide (2.25 l g., 0.008 m) in CH₂ Cl₂ (20 ml.) isadded dropwise at 0°-4° C. a solution of triflic anhydride (1.4 g.,0.0089 m) in CH₂ Cl₂ (15 ml.). After 15 minutes, (S)5-carbamoyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole (1.4g., 0.004 m) is added and the solution allowed to warm to roomtemperature. After stirring overnight at room temperature, the mixtureis poured into saturated Na₂ CO₃ (100 ml.) and the solution extractedwith CH₂ Cl₂ (3×400 ml.). The organic layer is dried over Na₂ SO₄,filtered and concentrated to dryness. The residue is chromatographed onalumina (activity grade II, E. Merck) and the product eluted with CHCl₃.The crude product is crystallized with maleic acid in IPA to yield 0.3g. (16%) of (S)5-cyano-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogenmaleate salt hemihydrate, m.p. 204°-6° C.

EXAMPLE 4 (S)Ethyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylatehydrogen maleate salt

Into a dry flask under N₂ is addedethyl-4-hydroxy-2-methylthiazole-5-carboxylate (20 g., 0.091 m), DMF(200 ml.) and NaH (50% mineral oil, 5.0 g., 0.104 m). After stirring for15 minutes, a solution of the tosylate of(S)-2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.106 m) inDMF (150 ml.) is added at room temperature and the solution heated on asteam bath with stirring. After 15 hours, the solution is cooled to0°-10° C., poured into H₂ O (1 l.) and extracted with ether (3×300 ml.).The organic layer is washed with H₂ O (2×150 ml.) and 1 N HCl (3×233ml.). The acid layer is added to NaOAc.3H₂ O (95 g., 0.7 m). After 5hours, the solution is extracted with ether (2×200 ml.), neutralizedwith saturated Na₂ CO₃ and extracted with CHCl₃ (3×300 ml.). The organiclayer is dried over Na₂ SO₄, filtered and concentrated to dryness. Theresidue is chromatographed on alumina (activity grade II, E. Merck) andthe product eluted with CHCl₃. The crude product is crystallized withmaleic acid in IPA-Et₂ O to yield 8.8 g. (21%) of (S) ethyl2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylatehydrogen maleate salt, m.p. 114°-116° C.

EXAMPLE 5 (S)5-Carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt

Using the same procedure described in Example 2B, (S) ethyl2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate(5.2 g., 0.015 m) MeOH (90 ml.) and liquid ammonia (33 g.) are heated toyield 0.9 g. (14%) of (S)5-carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt, m.p. 180°-2° C.

EXAMPLE 6 5Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt hemihydrate

A. Using the procedure of Example 2A, ethyl4-hydroxy-2-methylthiazole-5-carboxylate (9.35 g., 0.05 m), DMF (100ml.), NaH (57% mineral oil, 2.5 g., 0.052 m) and the tosylate of2-phenyl-3-tert.butylamino-2-hydroxymethyloxazolidine (0.053 m) in DMF(100 ml.) are reacted to yield 4.7 g. (30%) of ethyl2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate.

B. Using the procedure of Example 2B, ethyl2-methyl-4-(3-tert.-butylamino-2-hydroxypropoxy)thiazole-5-carboxylate(4 g., 0.014 m), MeOH (90 ml.) and liquid NH₃ (33 g.) are heated toyield 1.3 g. (22%) of5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt hemihydrate, m.p. 177°-78° C.

EXAMPLE 7 (S)5-Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt

A. Using the procedure of Example 2A, ethyl4-hydroxy-2-methylthiazole-5-carboxylate (28 g., 0.15 m), DMF (500 ml.),NaH (50% mineral oil, 7.5 g., 0.16 m) and the tosylate of (S)2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.15 m) in DMF(100 ml.) are reacted to yield 9.8 g. (20%) of (S) ethyl2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate.

B. Using the procedure described in Example 2B, (S) ethyl2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate(9.8 g., 0.034 m), methanol (185 ml.) and liquid NH₃ (8.5 g.) are heatedto yield 3.6 g. (29%) of (S)5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt, m.p. 161°-163° C.

EXAMPLE 8 (S)5-Cyano-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogenmaleate salt

Using the procedure described in Example 3, triphenylphosphine oxide(2.78 g., 0.01 m) in CH₂ Cl₂ (20 ml.), and (S)5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole (1.4g., 0.005 m) are reacted to yield 0.9 g. (47%) of (S)5-cyano-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogenmaleate salt, m.p. 172°-174° C.

EXAMPLE 9 (S)5-Methyl-2-(4'-pyridyl)-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole

Using the procedure in Example 2A,4-hydroxy-5-methyl-2-(4'-pyridyl)thiazole (3.65 g., 0.019 m), DMF (50ml.), NaH (57% mineral oil, 0.95 g., 0.02 m) and the tosylate of (S)2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (0.02 m) in DMF(20 ml.) are reacted to yield 0.6 g. (10%) of (S)5-methyl-2-(4'-pyridyl)-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole,m.p. 102-104.

EXAMPLE 10 (S) Ethyl4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogenmaleate salt hemihydrate

To a solution of (S) ethyl2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate(3.6 g., 0.01 m) in 3 N HCl (20 ml.) is added portionwise with stirringzinc dust (2.6 g.). After 3.5 hours at room temperature, the mixture ispoured into saturated Na₂ CO₃. The suspension is filtered and the filterpad washed well with CHCl₃. The aqueous layer is extracted with CHCl₃(3×75 ml.). The combined CHCl₃ extracts are dried over Na₂ SO₄, filteredand concentrated to dryness. The residue is chromatographed on silicagel and the product eluted with CHCl₃ saturated with aqueous ammonia.The crude product is crystallized with maleic acid in EtOH-Et₂ O toyield 0.4 g. (9%) of (S) ethyl4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogenmaleate salt hemihydrate, m.p. 103°-105° C.

EXAMPLE 11 (S)5-Carbamoyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole

Using the procedure described in Example 10, (S)5-carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole(1.7 g., 0.005 m), 3 N HCl (10 ml.) and zinc dust (0.94 g.) are reacted.Extraction of the aqueous layer with ether yielded unreacted startingmaterial while extraction next with CHCl₃ yielded 0.7 g. (48%) of5-carbamoyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole.

EXAMPLE 12 (S) 5-Cyano-4-(3-tert.butylamino-2-hydroxypropoxy)thiazolehydrogen maleate salt

Using the procedure described in Example 3, triphenylphosphine oxide(1.42 g., 0.005 m) in CH₂ Cl₂ (10 ml.), triflic anhydride (0.78 ml.,0.005 m) in CH₂ Cl₂ (10 ml.) and (S)5-carbamoyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole (0.7 g.,0.0026 m) are reacted to yield 0.18 g. (19%) of (S)5-cyano-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleatesalt, m.p. 168°-170° C.

Claims to the invention follow.

What is claimed is:
 1. Compounds having the formula ##STR17## andpharmaceutically acceptable salts thereof, wherein R is hydrogen, C₂-C₁₂ alkanoyl benzoyl, naphthoyl, methylbenzoyl or phenylbenzoyl,R₁ isC₁ -C₁₂ alkyl, R₂ is hydrogen, CF₃, C₆ -C₁₀ carbocyclic aryl selectedfrom phenyl, methylphenyl, halophenyl, nitrophenyl, methoxyphenyl,indanyl and naphthyl, C₁ -C₆ alkyl, C₁ -C₆ alkylthio, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, thienyl and furfuryl, R₃ is C₁ -C₆alkyl, --COOC₁ -C₆ alkyl, COOC₆ -C₁₂ aryl, or C₆ -C₁₀ carbocyclic arylwherein aryl is selected from phenyl, methylphenyl, biphenylyl andindanyl cyano or CF₃ provided that when R₂ is phenyl, R₃ is other thanC₁ -C₆ alkyl or COOC₁ -C₆ alkyl.
 2. Compounds of claim 1 wherein R ishydrogen.
 3. Compounds of claim 2 wherein R₁ is C₃ -C₄ branched chainalkyl.
 4. Compounds of claim 3 wherein R₂ is C₁ -C₆ alkyl.
 5. Compoundsof claim 3 wherein R₂ is C₆ -C₁₀ carbocyclic aryl.
 6. Compounds of claim3 wherein R₂ is C₁ -C₆ alkylthio.
 7. Compounds of claim 6 wherein R₃ is--COOC₂ H₅.
 8. Compounds of claim 3 wherein R₃ is CN, or C₁ -C₆ alkyl.9. Compounds of claim 8 wherein R₃ is --CN.
 10. Compounds of claim 3wherein R₁ is t-butyl, R₂ is phenyl and R₃ is --CN.
 11. The compounds ofclaim 3 wherein R₁ is t-butyl, R₂ is CH₃ --S-- and R₃ is --COOC₂ H₅. 12.The compounds of claim 3 wherein R₁ is t-butyl, R₂ is --CH₃ and R₃ is--CN.
 13. The compounds of claim 3 wherein R₁ is t-butyl, R₂ is H and R₃is --CN.
 14. Compounds of claim 1 having the S-isomer configuration. 15.A pharmaceutical composition for effecting β-adrenergic blockadecontaining an effective amount of a compound of claim 1 and conventionalcompounding ingredient.
 16. A pharmaceutical composition for effectingimmediate human antihypertensive response containing a compound of claim1 having the formula ##STR18## and conventional compounding ingredient.17. A method for effecting β-adrenergic blockade in a human whichcomprises administering an effective amount of a composition of claim15.
 18. A method for producing immediate onset antihypertensive inhumans which comprises administering an effective amount of claim 16composition.